Escherichia coli in Iran: An Overview of Antibiotic Resistance: A Review Article.

Background
Escherichia coli is the most prominent cause of infectious diseases that span from the gastrointestinal tract to extra-intestinal sites such as urinary tract infection, septicaemia, and neonatal meningitis. The emergence and spread of antibiotic resistance in E. coli is an increasing public health concern across the world. Rising resistance in E. coli isolates is also observed in Iran. This review summarizes the status of antibiotic resistance of E. coli isolates in Iran from 2007 to 2016.


Methods
The data of the prevalence of E. coli antibiotic resistance were collected from databases such as Web of Science, PubMed, Scopus, Embase, Cochrane Library, Google Scholar and Scientific Information Database.


Results
Antibiotic resistance in E. coli is on the rise.


Conclusion
Prevalence of antibiotic resistance of E. coli varies from region to region in Iran.


Introduction
Over the past decade increasing antibiotic resistance among isolates of Enterobacteriaceae has become a main public health concern (1). In the most recent estimates of global antibiotic resistance published by the WHO in 2014, Escherichia coli was named as one of the biggest concerns associated with hospital and communityacquired infections (2). Pathogenic E. coli is one of the major causes of infectious diseases that span from the gastrointestinal tract to extra-intestinal sites such as the urinary tract, bloodstream, and central nervous system (3,4). E. coli is the most common producers of Extended-Spectrum Beta-Lactamases (ESBLs) (5). The presence of ESBLs enzymes compromises the efficacy of all β-lactams, excepting cephamycins and carbapenems, by hydrolysis of the β-lactam ring, and play a major role in the inhibition of the penicillin-binding protein targets (6). More than 300 different ESBL enzymes have been recognized so far (7). Since the early 2000s, CTX-M enzymes have been increasingly detected, and these enzymes have now replaced other ESBLs such as TEM and SHV as the most common type of ESBL (6,8). Other enzymes having ESBL have also been described (e.g. PER, VEB-1, BES-1, CME-1, SFO-1, and GES-1) (9). Due to the rising percentage of bacteria-carrying ESBL genes, there has been a corresponding increase in the clinical use of antibiotics of the carbapenem group. The hallmark of carbapenemases enzymes is its ability to inactivate carbapenems and extended-spectrum cephalosporins (10).
Metallo-β-lactamase (MBLs) enzymes are now widespread and found in Asia, Europe, Canada, Australia, and South and North America (11). The fluoroquinolones are potent antibiotic agents used in the prophylaxis and treatment of infections caused by E. coli. Fluoroquinolone-resistant E. coli strains often indicate resistance to all main classes of available antimicrobials such as gentamicin, tetracycline, ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole (12). The aminoglycosides are powerful bactericidal agents often used along with a spectrum beta-lactams. Resistance to aminoglycosides is most commonly caused by aminoglycoside modifying enzymes such as phosphorylate (aminoglycoside phosphoryl transferase [APH]), acetylate (aminoglycoside acetyltransferase [AAC]) or adenylate (aminoglycoside nucleotidyltransferase [ANT]) (13). The genes encoding resistance to sulfonamideclass antibiotics such as sul1, sul2, and sul3, which competitively inhibit dihydropteroate synthetase activity, are highly prevalent among Gramnegative bacteria isolated from human samples (14). Unfortunately, the sul genes have the highest prevalence in E. coli isolates (14,15). Trimethoprim (TMP) inhibits dihydrofolate reductase that catalyses the formation of tetrahydrofolate from dihydrofolate. The most prevalent of the dhfr genes, dhfrI and variants of dhfrII, mediate high-level resistance to TMP and are most frequently found in Gram-negative enteric bacteria (16). The purpose of this review was assessing the exact magnitude of E. coli antibiotic resistance in peer-reviewed published literature in Iran over the last nine years.

Inclusion and exclusion criteria
All original articles that presented cross-sectional or cohort studies and reported the prevalence of antibiotic resistance of E. coli in Iran were considered.

Data analysis
The analysis for the descriptive data was carried out using SPSS software (Chicago, IL, USA, ver. 19).

Results and Discussion Epidemiology of antibiotic resistance
In 2015 the Eastern Mediterranean regional office of WHO reported that none of the participating countries had a national action plan for antimicrobial resistance, considered a priority and an outcome indicator for control measures (17). In Iran, like other Eastern Mediterranean countries, antibiotics can easily be obtained over the counter. Antimicrobial medicines are often prescribed at the request of patients, and pharmacies do not necessarily comply with regulations. Many people in the Eastern Mediterranean region believe that antibiotics help in most ailments with fever. Poorquality and counterfeit antimicrobial medicines are a particular problem with respect to antimicrobial resistance in these regions (17)(18)(19). In Iran antibiotic resistance in Gram-negative bacteria is on the rise, particularly in E. coli (20)(21)(22)(23). Different patterns of antibiotic resistance is seen in various regions across the Iran: For example, more than 90% of E. coli isolates were resistant to penicillin (ampicillin or amoxicillin) in Tehran (capital) (24, 25) ( Table 1). The rate of resistance of E. coli isolates in four countries to third-generation cephalosporins was 22%-63% (2). Many studies conducted in Iran have also revealed a similar resistance rate of E. coli isolates to third-generation cephalosporins in various regions (26,(28)(29)(30)(31)(32) (Table 1). In Iran, cephalosporins are widely used because of their low rate of side effects. This may be related to the increased resistance to these antibiotics (33).  The presence of blaIMP, blaVIM, and blaNDM-1 genes from EAEC isolates in children were reported and none of the isolates possessed these genes (44). None of the ESBL-producing E. coli isolates were positive for blaIMP and blaVIM in Kerman, southeastern Iran (39). The distribution of resistance genes among E. coli isolates is summarized in Table 2.
qnrA (0.00), qnrB (6.66), qnrS (5.00) (38) qnr ( The prevalence of isolates resistant to aminoglycosides ranged from 0.00% among EPEC isolated from children (Tehran, capital) (45) to 77.27% among E. coli isolated from Cervico-vaginal (Zabol, south-eastern Iran) (46). The percentage is also higher in Zahedan (south-east) (43), Karaj (north) (47), and Tabriz (north-west) (48). Among aminoglycoside-modifying enzymes, resistance against gentamicin, kanamycin, cidomycin, and tobramycin in E. coli is mediated by ANT (2")-Ia enzyme, coded by ant(2")-Ia gene. aac (6')-Ib gene is more common and leads resistance to kanamycin, tobramycin, and amikacin; Simultaneous resistance to gentamycin and tobramycin mediated by AAC(3)-IIa enzyme coded by aac(3)-IIa gene (49). The prevalence of different resistance genes varied-96.10% for the aadA1 gene (42), 68.03% for the aac(3)-IV gene (50), 78.87% for the aac(3)-IIa gene, and 47.88% for the ant(2)-Ia gene (49). Nalidixic acid is an antibiotic from the first generation of quinolones. Nowadays resistance to this antibiotic has increased substantially across Iran (26,43,46,47,(51)(52)(53)(54). Fluoroquinolones are highly efficacious antimicrobial agents, often preferred as initial agents for empirical therapy of UTIs. Unfortunately, urinary tract E. coli isolates in both hospitalized and outpatients are becoming increasingly resistant to commonly used fluoroquinolones (55,56). The prevalence of fluoroquinolone-resistant isolates ranged from about 1%-3% (45,50,57) to more than 50% in Iran (32,55,58,59). qnr genes (qnrA, qnrB, and qnrS) may facilitate the spread and increase the prevalence of quinolone-resistant strains. To date, qnr genes have been widely iden-tified in Southern and Eastern Asia (82,60). In earlier studies in Iran, the most prevalent gene among all isolates was qnrA, followed by qnrB and qnrS (40,60). qnrS has been reported previously from clinical isolates of E. coli in Mashhad (60) and has also been detected in UTI isolated from children E. coli isolates from Hamadan (38). Our pooled evidence showed that the prevalence of macrolide resistance among E. coli clinical isolates varied from 0%-3% in Tehran (sample source: STEC), Hamadan (UTI from children), and Jahrom (urine from children) to 94% in Tehran (various clinical samples) (25, 50, 61, 62) (Table 1). In a study in Tehran, 39% of E. coli isolates were resistant to aztreonam (25). Resistance against aztreonam may be related to the production of ESBL enzymes by ESBL-producing strains (53). Uropathogenic E. coli strains showed high sensitivity to nitrofurantoin (47,50,53). Susceptibility to nitrofurantoin may result from decreasing the use of this drug in Iran (53). The rate of colistin-resistant ESBL-Producing E. coli with the MIC test was 82% (63). Increasing use of colistin for treatment of various infections due Gram-negative bacteria has led to the emergence of colistin resistance in several countries Asia (especially Korea and Singapore) (64). Percentages of E. coli isolates resistant to cotrimoxazole vary with the geographical location of the patients: 93.40% in Kerman (65) and 4.20% in Tehran (45). Among clinical E. coli isolates resistance to TMP varies greatly, ranging from 10% to 70% depending on geographical locations (66). A high prevalence of clinical resistance to TMP (dfrA1 gene) was reported in enteric bacteria (14,42,50,67). Only one city (Tehran) reported a decreasing trend (21.95%) (68). Resistance to sulfonamide was one of the most common resistances detected by previous studies and is often associated with the acquisition of the resistance genes sul1 and sul2 (14,50). High prevalence of tetracycline resistance has been observed in E. coli isolated from human and animals around the world (69). Prevalence of tetA is higher than tetB gene in E. coli strains isolated from clinical samples (42,50,68). The most developed countries have sufficient control of over-the-counter sales, while many drugs, including antibiotics, are easily available in many developing countries. In Iran, as in other developing countries, almost any antibiotic can be acquired over the counter without a prescription (19). In other cases, doctors might not advise laboratory tests to confirm bacterial infection and hence the antibiotic might be unnecessarily prescribed (70).

Conclusion
Over the years, antimicrobial resistance in Iran has increased markedly in Gram-negative bacteria such as E. coli. This prevalence of antibiotic resistance of E. coli varies from region to region in Iran. However, it cannot fully represent the prevalence of antibiotic resistance of E. coli in Iran, because the extent of resistance to different antibiotic categories is yet to be examined in many areas of the country.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the author.